High-Resolution Analysis of Parent-of-Origin Allelic Expression in the Mouse Brain

Sex-Specific Parent-of-Origin Allelic Expression in the Mouse Brain

Christopher Gregg1,2 Jiangwen Zhang,3 James E.Butler,1,2 David Haig,4 and Catherine Dulac1,2 * 

Sex-Specific Parent-of-Origin Allelic Expression in the Mouse Brain

Mohamed Antar Aziz MohamedLaboratory of Molecular Biology

2012310880

Sex-Specific Parent-of-Origin Allelic Expression in the Mouse Brain

Introduction

Results

Discussion

Introduction

What is Epigenetics?

“Any process that alters gene activity without changing the DNA sequence, and leads to modifications that can be transmitted to

daughter cells”

Introduction

Gene silencing

X-chromosome inactivation

Genomic Imprinting

Epigenetic Processes

Genomic Imprinting

What is Genomic Imprinting?

Genomic imprinting is an epigenetic mode of gene regulation involving preferential expression of the paternally or

maternally inherited allele.

Why Genomic Imprinting is important? Because many imprinted genes are associated with embryonic

growth, development feeding and motivated behaviors, and parental biases preferentially target genetic pathways

governing metabolism and cell adhesion.

Both produced by same genetic mutation

Prader-Willi/Angelman syndrome

*AS: deletion of maternal copy, maternal mutation of UBE3A gene or UPD of chromosome 15q11-q13

*Severe mental retardation, happy demeanor, non-verbal

*PWS: deletion of paternal copy or UPD of chromosome 15q11-q13

*Language, motor and developmental delays, excessive weight gain

Sexual dimorphism is a central characteristic of mammalian brain function and behavior that influences major neurological diseases in humans.

Three processes may underlie sexually dimorphic genomic imprinting.

Nonrandom X inactivation.

Imprinting of individual X-linked loci in females .

Autosomal genes might be imprinted in one sex but not the other.

ResultsImprinted gene expression in the adult CNS.

Results

A high-resolution approach to analyze imprinting.

Illumina RNA-sequencing (RNA-Seq) technology to characterize the transcriptome of brain tissues from F1 hybrids resulting from reciprocal crosses of CAST/EiJ (CAST) and C57BL/6J (C57) mice [F1 initial cross (F1i): CAST mother × C57 father; F1 reciprocal cross (F1r): C57 mother × CAST father].

F1i CAST (mother) X C57 (father) F1r C57 (mother) X CAST (father)

Identification of loci exhibiting parent-of-origin allelic effects in the embryonic and adult CNS using Illumina RNA-Seq.

Sex-specific imprinting and preferential expressionof the Xm in the female brain.

This elevated expression from the Xm versus the Xp may indicate a bias in X inactivation in the brain, a hypothesis further investigated with a transgenic mouse line expressing X-linked egfp under the control of the cytomegalovirus (CMV) promoter as a reporter of the active X chromosome.

Preferential expression of Xm in female cortical regions indicated by Xmegfp/Xp and Xm/Xpegfp transgenic mice.

Cortex

Hypothalamus

Sex-specific imprinted autosomal genes were uncoveredin the adult male and female POA and mPFC.

Sex-specific imprinted expression of Mrpl48 and Il18 in the female brain.

Illumina read data for an imprinted SNP in the 3 untranslated region (3 UTR) of Mrpl48′ ′

Illumina read data for the imprinted SNP in ll18

QPCR analysis of Il18 expression in maternal- versus paternal-deletion Il18 heterozygous mice on C57

background

DiscussionPrevious data present evidence for epigenetic mechanisms by which parents may differentially influence gene expression in the brain of daughters versus sons and provide insights into sexually dimorphic epigenetic pathways recently uncovered in the brain.

The X chromosome is enriched for genes involved in brain function. Investigating the potential relations between maternal and paternal gene expression programs may shed light on brain function, evolution, and disease.

Finally